NMR is a field of science with applications ranging from basic physics and chemical analysis to medical imaging and diagnostics (MRI). NMR relies on picking up RF signals from nuclear spins transiting between energy levels created as an external magnetic field is applied. The spectral properties of the NMR signal are highly influenced by the microscopic environment of the observed nuclei hence providing detailed information on that environment. This gives NMR its informative power, unparalleled by any other spectroscopic technique.
Despite this, NMR suffers from an inherently low SNR which poses severe limitations on its applicability. An NMR sample must be relatively large and materials found in it in trace amounts cannot be detected, despite the great importance they might have. Such is the case, e.g., in the investigation of surfaces, a thriving scientific field in its own right. The actual amount of material found at the surface is a very small percentage of most samples. But virtually all dynamical processes, such as catalysis or corrosion, occur at the surface. So, to access the surface with NMR spectroscopy is an important scientific goal that cannot be achieved with regular magnetic resonance. The SNR problem is also encountered in the MRI field, where the low sensitivity limits the scope of the measurement only to the bulk constituents of the human body, i.e., water and fat. All the interesting parts, such as proteins, hormones, genetic material, etc., are usually completely transparent, unless extremely specialized and unique protocols are employed. The sensitivity problem is also the bottle neck factor limiting image resolution.
The low SNR also mandates that multiple identical measurements be averaged out in order to reach a reasonable prominence of the data. This renders NMR measurements very lengthy in time, and their length usually grows exceedingly with the complexity of the examined system. Some “holy grail” applications such as metabolic MRI or advanced quantum computing are not even attempted due to ridiculously long experiment durations. Implementation of sophisticated measurement protocols, two-dimensional NMR for instance, is hindered substantially by the lengthiness problem. In MRI, this problem is manifested in very lengthy examinations, which are uncomfortable for the patients and reduce the availability of MRI examinations. It also comes into play when one wishes to take rapid scans in order to image body parts as they move (e.g., heart MRI).
The above examples illustrate that the SNR-sensitivity problem is of central importance in the NMR field whether in its scientific research branch or in its medical branch. The circumvention of this acute problem is thus of great importance and several techniques aimed at it are present. Those techniques are often referred to as hyperpolarization techniques and include, e.g., para-hydrogen, pre-polarization, optical pumping, and DNP.
DNP is a technique that enables the transfer of magnetization from a highly polarized population of unpaired electron spins, known as polarizing agents, onto the much more weakly polarized population of nuclear spins (Maly et al., 2008; Abragam and Goldman, 1978). Since its first demonstration as a manifestation of the Overhouser effect in low fields (Carver and Slichter, 1956), DNP has attracted much interest both as means to dramatically increase the faint NMR signal (Ardenkjær-Larsen et al., 2003) and as a scientifically interesting phenomenon in its own right (Hu et al., 2011). Consequently, DNP has found recent applications ranging from structural biology (Barnes et al., 2008) and NMR of surfaces to experimental metabolic MRI used for clinical diagnosis (Nelson et al., 2013; Mishkovsky et al., 2012; Golman et al., 2006). The magnetization enhancement factor for protons obtainable by DNP, which is calculated as the ratio between the hyper-polarized and the normal thermal (Boltzmann) magnetizations, has a theoretical maximal value of ˜658. In practice, however, enhancement factors are usually several times smaller than the maximal theoretical ones (typically 10-100). An increase in magnetization by a given factor speeds up the NMR experiment quadratically, and in this respect the hyper polarization obtained by DNP is of great value.
The common method of obtaining efficient DNP enhancements in molecules of interest is to dissolve them in the presence of unique stable free radicals (polarizing agents) (Maly et al., 2008; Song et al., 2006) and then cool the solution to low cryogenic temperatures, where an appropriate microwave irradiation resonant with free radicals can transfer the spin polarization from the electrons to the nuclei of interest (Maly et al., 2008; Abragam and Goldman, 1978). Following this, the sample can be measured as is, using solid state NMR (Barnes et al., 2008), or undergo rapid dissolution to be measured in the liquid state (Ardenkjær-Larsen et al., 2003), while preserving most of its spin polarization. This fairly established procedure is very effective, but yet possesses some challenges: The most trivial hindrance stems from the polarizing agents' chemical uniqueness and cost, which can amount to hundreds of dollars per milligram for some species. A more profound problem that plagues the use of DNP is the necessity to achieve molecular-level mixing between sample molecules and polarizing agents, obtainable only in a solvent environment. Given that this is not always the native environment of the sample, much care and experimental optimization must be exercised in order to arrive at a successful DNP experiment whilst preserving the sample's key features (Lesage et al., 2010). Furthermore, a highly serious problem concerns the use of DNP for medical purposes, due to the incompatibility of existing stable radicals with the human body, and thus severely limits the introduction of the DNP technique into the clinic (Dollmann et al., 2010). While several solutions to this problem exist in various stages of maturity (Dollmann et al., 2010; Eichhorn et al., 2013; Ardenkjaer-Larsen et al., 2011), they are far from being comprehensive.
In light of the above, it might be highly beneficial to supplement the current arsenal of polarizing agents with additional, preferably endogenic, types that are complementary to the existing ones, and without going through the solution phase.
International Publication No. WO 2014139573 discloses a method for the preparation of highly polarized nuclear spins containing sample, aimed at enhancing the SNR in NMR and MRI measurements thus shortening these measurements. The concept underlying the method disclosed is the generation of radicals in the solid state, which are then used in a DNP process prior to the NMR measurement or MRI scan. This method necessitates the presence of carbonyl groups on the material treated, more particularly, the alpha- and/or gamma-diketone functional groups R1—C(O)—C(O)—R2 and R1—C(O)—C═C—C(O)—R2, respectively, and uses electromagnetic irradiation in the visible or UV range so as to generate radicals from those carbonyl groups. According to this publication, the irradiation process takes about an hour or more.
Another method of relevance achieves DNP of solid samples without dissolving them in solution by impregnating powdered sub-micron sized samples with non-solvents (Rossini et al., 2014). However, the impregnation steps and sample grinding can cause phase transitions between polymorphs in some cases (Pinon et al., 2015).